Normal development and functions of immune cells require adenosine deaminase (ADA) activity. The absence or low levels of ADA in humans result in severe combined immunodeficiency (SCID), which is characterized by hypoplastic thymus, T lymphocyte depletion, and autoimmunity. Accumulation of intracellular adenosine and deoxyadenosine and their direct lymphotoxicity are believed to be responsible for the detrimental effects on T cells observed in ADA SCID patients; however, mechanisms of uniquely high susceptibility of immune cells to effects of ADA deficiency have not been completely understood. We proposed that T cell depletion in ADA SCID patients could be at least partially explained by inhibition of T cell activation in the ADA-deficient environment by extracellular adenosine. In support of this model we found, that extracellular adenosine inhibits TCR-triggered activation of thymocytes under conditions of ADA deficiency both in vitro and on vivo. Strong evidence against the intracellular lymphotoxicity of adenosine in these conditions is provided by the "rescue" of adenosine-exposed thymocytes from TCR-triggered apoptosis. Unexpectedly, adenosine strongly inhibited TCR-triggered activation of A2aR-deficient thymocytes in the presence of ADA inhibitors suggesting the involvement of A2a receptor independent pathway of effects of adenosine on T cells in ADA-deficient environment.